This project sets out to test two hypotheses: (1) Immunologically mediated diabetes in the NOD mouse results from CD4 T cell- dependent inflammatory tissue damage. The proximate cause of diabetes is free-radical mediated beta cell damage. We test hypothesis (1) by determining the phenotype of cells responsible for the transfer of the disease to non-diabetic NOD mice, and disease recurrance in islet tissue transplanted to diabetic NOD recipients. Confirmation of involvement in the disease process comes from in vivo biological studies of T cell lines and clones, derived from diabetic NOD mice. The mechanism of islet damage will be approached by investigating implications of the Okamoto model for inflammatory islet damage. This model postulates that damage results from free-radical production in the region of the beta cell. These radicals cause DNA breaks, which in turn activate a DNA repair enzyme and result in a depletion of NAD levels in the cell. As a result proinsulin synthesis in inhibited and the beta cell becomes even more sensitive to radical damage.